American Association for Cancer Research
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Supplementary figure legend from RAS/MAPK Activation Is Associated with Reduced Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer: Therapeutic Cooperation Between MEK and PD-1/PD-L1 Immune Checkpoint Inhibitors

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journal contribution
posted on 2023-03-31, 18:49 authored by Sherene Loi, Sathana Dushyanthen, Paul A. Beavis, Roberto Salgado, Carsten Denkert, Peter Savas, Susan Combs, David L. Rimm, Jennifer M. Giltnane, Monica V. Estrada, Violeta Sánchez, Melinda E. Sanders, Rebecca S. Cook, Mark A. Pilkinton, Simon A. Mallal, Kai Wang, Vincent A. Miller, Phil J. Stephens, Roman Yelensky, Franco D. Doimi, Henry Gómez, Sergey V. Ryzhov, Phillip K. Darcy, Carlos L. Arteaga, Justin M. Balko

Supplementary figure legend


Inflammatory Breast Cancer (IBC) Network Foundation

the Cure Foundation


Breast Cancer Specialized Program of Research Excellence

Vanderbilt-Ingram Cancer Center

Susan G. Komen for the Cure Foundation

the National Breast Cancer Foundation of Australia

Cancer Council Victoria, Australia



Purpose: Tumor-infiltrating lymphocytes (TIL) in the residual disease (RD) of triple-negative breast cancers (TNBC) after neoadjuvant chemotherapy (NAC) are associated with improved survival, but insight into tumor cell-autonomous molecular pathways affecting these features are lacking.Experimental Design: We analyzed TILs in the RD of clinically and molecularly characterized TNBCs after NAC and explored therapeutic strategies targeting combinations of MEK inhibitors with PD-1/PD-L1–targeted immunotherapy in mouse models of breast cancer.Results: Presence of TILs in the RD was significantly associated with improved prognosis. Genetic or transcriptomic alterations in Ras–MAPK signaling were significantly correlated with lower TILs. MEK inhibition upregulated cell surface MHC expression and PD-L1 in TNBC cells both in vivo and in vitro. Moreover, combined MEK and PD-L1/PD-1 inhibition enhanced antitumor immune responses in mouse models of breast cancer.Conclusions: These data suggest the possibility that Ras–MAPK pathway activation promotes immune-evasion in TNBC, and support clinical trials combining MEK- and PD-L1–targeted therapies. Furthermore, Ras/MAPK activation and MHC expression may be predictive biomarkers of response to immune checkpoint inhibitors. Clin Cancer Res; 22(6); 1499–509. ©2015 AACR.